Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

Self-assembled hydrogel fibers for sensing the multi-compartment intracellular milieu.

Targeted delivery of drugs and sensors into cells is an attractive technology with both medical and scientific applications. Existing delivery vehicles are generally limited by the complexity of their design, dependence on active transport, and inability to function within cellular compartments. Here, we developed self-assembled nanofibrous hydrogel fibers using a biologically inert, low-molecular-weight amphiphile. Self-assembled nanofibrous hydrogels offer unique physical/mechanical properties and can easily be loaded with a diverse range of payloads. Unlike commercially available E. coli membrane particles covalently bound to the pH reporting dye pHrodo, pHrodo encapsulated in self-assembled hydrogel-fibers internalizes into macrophages at both physiologic (37°C) and sub-physiologic (4°C) temperatures through an energy-independent, passive process. Unlike dye alone or pHrodo complexed to E. coli, pHrodo-SAFs report pH in both the cytoplasm and phagosomes, as well the nucleus. This new class of materials should be useful for next-generation sensing of the intracellular milieu.

Engineering the extracellular matrix for clinical applications: endoderm, mesoderm, and ectoderm.

Tissue engineering is rapidly progressing from a research-based discipline to clinical applications. Emerging technologies could be utilized to develop therapeutics for a wide range of diseases, but many are contingent on a cell scaffold that can produce proper tissue ultrastructure. The extracellular matrix, which a cell scaffold simulates, is not merely a foundation for tissue growth but a dynamic participant in cellular crosstalk and organ homeostasis. Cells change their growth rates, recruitment, and differentiation in response to the composition, modulus, and patterning of the substrate on which they reside. Cell scaffolds can regulate these factors through precision design, functionalization, and application. The ideal therapy would utilize highly specialized cell scaffolds to best mimic the tissue of interest. This paper discusses advantages and challenges of optimized cell scaffold design in the endoderm, mesoderm, and ectoderm for clinical applications in tracheal transplant, cardiac regeneration, and skin grafts, respectively.

Determining lower limits of detection of digital PCR assays for cancer-related gene mutations.

Digital PCR offers very high sensitivity compared to many other technologies for processing molecular detection assays. Herein, a process is outlined for determining the lower limit of detection (LoD) of two droplet-based digital PCR assays for point mutations of the epidermal growth factor receptor (EGFR) gene. Hydrolysis probe mutation-detection assays for EGFR p.L858R and p.T790M mutations were characterized in detail. Furthermore, sixteen additional cancer-related mutation assays were explored by the same approach. For the EGFR L8585R assay, the assay sensitivity is extremely good, and thus, the LoD is limited by the amount of amplifiable DNA that is analyzed. With 95% confidence limits, the LoD is one mutant in 180,000 wild-type molecules for the evaluation of 3.3 µg of genomic DNA, and detection of one mutant molecule in over 4 million wild-type molecules was achieved when 70 million copies of DNA were processed. The measured false-positive rate for the EGFR L8585R assay is one in 14 million, which indicates the theoretical LoD if an unlimited amount of DNA is evaluated. For the EFGR T790M assay, the LoD is one mutant in 13,000 for analysis of a 3.3 µg sample of genomic DNA, and the dPCR assay limit sensitivity approaches one mutant in 22,000 wild-type molecules.

Simulacion del proceso Kivcet Karachipampa bajo consideraciones de equilibrio termodinamico

El proyecto de grado: "Simulacion del proceso KIVCET Kachachipampa bajo consideraciones de equilibrio termodinamico:, tiene por objetivo principal, el de realizar el Balance masico termico del Reactor Kivcet de la Planta Metalurgica de Karachipampa de Potosi, usando para ello una herramienta de tipo computacional, es decir el apoyo de un programa de computadora, que sea capaz de resolver el complejo sistema de ecuaciones no lineales implicitas, envuelto en la solucion de los sistemas reaccionantes, en consideraciones de quilibrio termodinamico. El programa computacional llamado EQUILIB, ha sido escrito en el lenguaje de programacion Borland C++, habiendo demostrado su capacidad de resolver las incognitas planteadas durante la simulacion del proceso. EQUILIB ha sido creado sobre la base del modelo llamado de :Shimpo-Goto", con unas ligeras modificaciones, para que pueda ser aplicado al esquema de funcionamiento del Reactor Kivcet. Parala simulacion del Proceso Kivcet Karachipampa, el Reactor ha tenido que ser dividido en seis unidades diferentes, teniendo en cuenta las distintas condiciones de proceso para cada unidad en particular, este metodo llamado multi-etapa, ha demostrado ser provechoso en la presente simulacion, obteniendo resultados muy aceptables. La simulacion del proceso Kivcet con consideraciones de Equilibrio Termodinamico para el Horno Kivect de Portovesme, demuestra que las ecuaciones termodinamicas por si solas, obtienen resultados relativamente aceptables para poder predecir la cantidad de polvo producido en el Horno Flash, esto en realidad es debido, a que no se considera el arrastre mecanico de polvos por el flujo turbulento de gas, estando su obtencion sujeta a los respectivos trabajos de operacion de la Planta, no obstante, se puede observar el poder de la simulacion, en la interpretacion de los resultados, ya que predice con bastante aproximacion las calidades de la escoria, el metalico y los humos del Horno Electrico, asi como las cantidades y calidades del bano del flash y los humos de la camara de enfriamiento de gases de salida. El analisis de resultados de simulacion para el Horno Kivcet de Portovesme, demuestra que el modelo termodinamico tiene una aproximacion aceptable para la prediccion del comportamiento de cualquier reactor Kivcet. El analisis de los resultados del balance masico, ha demostrado que habra una desulfurizacion aceptable en la suspension del flash, estando el bano casi libre del elemento azufre, evitando de este modo la formacion de mata en la solera del horno electrico.